Solid solution perforator for drug delivery and other applications

ABSTRACT

A solid drug solution perforator (SSP) system and an associated drug reservoir are provided for delivering therapeutic, prophylactic and/or cosmetic compounds, for nutrient delivery and for drug targeting. For drug delivery, the SSP system includes an active drug ingredient and a matrix of perforator material that biodegrades or dissolves quickly upon contact with a patient&#39;s body. The SSP system provides a skin barrier perforator and a controller for prompt initiation and cut-off drug delivery. In a preferred method of transdermal drug delivery, an SSP system containing a selected drug penetrates into an epidermis or dermis, and the drug is promptly released from the (dissolving) SSP system perforator. An additional drug is optionally delivered from a patch reservoir through skin pores created by insertion of the perforator. Formulation and fabrication procedures for the SSP and associated reservoir are also provided. An SSP system can be fabricated with variety of shapes and dimensions.

FIELD OF THE INVENTION

[0001] This invention relates to controlled delivery of one or moredrugs to, and diagnosis of fluids in, a patient's body.

BACKGROUND OF THE INVENTION

[0002] Many new drugs, including proteins, peptides and DNAconstituents, have been developed for better and more efficienttreatment for disease and illness. Especially due to recent advances inmolecular biology and biotechnology, increasingly potent pharmaceuticalagents, such as recombinant human insulin, growth hormone anderythropoeitin are available. However, a major limitation in using thesenew drugs is lack of an efficient drug delivery system; a drug must betransported across one or more biological barriers in the body at ratesand in amounts that are therapeutically effective.

[0003] Most drugs are orally administered. However, some drugs,especially protein and peptide drugs, cannot be effectively adsorbed inthis manner because of severe degradation in the gastrointestinal tract,poor absorption in intestinal membrane and/or first pass breakdown bythe liver.

[0004] Another administration technique is parental injection, usingstandard syringes or catheters. Needle injection provokes needle phobia,substantial pain, local damage to the skin in many patients. Withdrawalof body fluids, such as blood, for diagnostic purposes provokes similardiscomforts. Further, needle injection is not ideal for continuousdelivery of a drug, or for continuous diagnosis.

[0005] Another drug delivery technique is transdermal delivery, whichusually relies on diffusion of a drug across the skin. This method isnot broadly applicable because of the poor skin permeability of manydrugs. The outermost layer of skin, stratum corneum, represents a majorbarrier to transdermal drug penetration. Once a drug reaches the dermaldepth (below the epidermal layer), the drug diffuses rapidly to deeptissue layers and other parts of the system via blood circulation.

[0006] In an attempt to improve the rate of drug delivery through theskin, chemical enhancers, iontophoresis, electroporation, ultrasound,and heat elements have been used to supplement drug delivery. However,these techniques are not suitable for some types of drugs and often failto provide a therapeutic level of delivery. These techniques sometimesresult in undesirable skin reactions and/or are impractical forcontinuous controlled drug delivery over a period of hours or days.

[0007] Other attempts, such as particle or liquid injection, have beenmade to design alternative techniques to transfer drugs transdermally. Amain advantage of those techniques is absence of needle use andreduction of incidence of contamination. However, liquid injectionfrequently causes some pain and/or sub-dermal hemorrhage. One technique,ballistic particle injection, is hard to administer exactly andcontinuously and can cause micro-bleeding.

[0008] Other attempts, such as micro-needle drug delivery, have beendeveloped using micro-fabrication procedures from the semiconductorindustry. While the conventional devices have some uses, most of thesedevices are designed for drug delivery through a hollow interior of aneedle or along an outer surface of a needle. However, because most ofthese needles are made from brittle silicon materials, needle breakageunder the skin is a possibility. Some devices are used as skinperforators for subsequent patch drug application. There remains a needfor better drug delivery devices that rely on smaller incisions, deliverdrug with greater efficiency and less variability of drugadministration, and/or are easier and safer for a patient to use.

[0009] What is needed is an approach that reduces or controls the skinbarriers to permit controlled introduction of one, two or more drugs,simultaneously or sequentially, and to provide prompt initiation andcut-off of drug delivery with improved efficiency and safety.

SUMMARY OF THE INVENTION

[0010] These needs are met by the invention, which applies mechanicalpenetration of the skin, using a solid solution perforator (“SSP”)system including an array of one or more needles, blades or otherperforators that include a drug as part of a solid solution perforatorand dissolve or undergo biodegradation relatively quickly. An “SSPdevice” optionally includes a reservoir of a second drug, contained in apatch, located adjacent to the perforator array and containing eitherthe same drug as is contained in the SSP system perforators or adifferent drug. By creating a drug transport channel or port in theskin, especially in the outermost layer, through use of an SSP (system)perforator, the barrier properties of skin can be diminished orcontrolled for drug delivery and for providing access to body fluids tobe monitored. Optionally, a patch includes a ring of adhesive that bondswith, and holds the reservoir against, the patient's skin adjacent tothe perforated region of the skin. The patch system is separatelyactivated to deliver the second drug through the skin channels(s) formedby the SSP perforator(s).

[0011] In contrast to conventional hollow needle technologies, the SSPsystem includes a solid matrix of dissolvable (including meltable) orbiodegradable material that optionally holds one or more selected drugsand is formed into one or more perforators. The matrix can be composedof fast-dissolving and/or swelling materials. For drug deliveryapplication, the SSP system includes an active drug that dissolvesreasonably quickly and leaves the channel open for subsequent drugdelivery, or to collect and monitor body fluids or other analytes. AnSSP perforator can be 100 percent drug or a mixture of drugs, dependingupon the application and physical/chemical properties of the drug(s).Inclusion of a swelling component in the matrix can keep the channelopen even longer. The solid solution can be a homogeneous ornon-homogeneous phase or porous solid solution, for example, a solidmade from an emulsion or suspension.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a schematic cross-section of a patient's skin.

[0013] FIGS. 2A-2G are perspective views of examples of suitable SSPperforators that can be used in the invention.

[0014]FIG. 3 is a plan view of an array of perforators and a surroundingannular ring of adhesive that are part of an SSP system.

[0015] FIGS. 4-9 illustrate activation mechanisms that can be used forSSP skin penetration according to the invention.

[0016]FIG. 10 illustrates a drug reservoir system according to theinvention.

[0017] FIGS. 11A-11C and 12A-12F illustrate operation of patch systemsthat can be used as part of the invention.

DESCRIPTION OF BEST MODES OF THE INVENTION

[0018]FIG. 1 is a cross-sectional view of the top layers of the skin 11,including a stratum corneum 13, an epidermal layer or epidermis 15 and adermal layer or dermis 17. The outermost layer of skin, the stratumcorneum 13, is a dead cell layer, usually between 10 and 20 microns (μm)thick. The stratum corneum 13 contains hydrophilic keratinocytessurrounded by a hydrophobic extra-cellular matrix of lipids, mainlyceramide. Due to the structural and compositional uniqueness, thestratum corneum 13 presents the greatest barrier to transdermal flux ofdrugs or other molecules into the body, and of body fluids and otheranalytes out of the body. The stratum corneum 13 is continuously renewedby shedding of corneum cells, with an average turnover time of 2-3weeks.

[0019] Below the stratum corneum 13 is the viable epidermis or epidermallayer 15, which is between 50 and 100 μm thick. The epidermis containsno blood vessels and freely exchanges metabolites by diffusion to andfrom the dermis 17, located immediately below the epidermis 15. Thedermis is between 1 and 3 mm thick and contains blood vessels,lymphatics, and nerves. Once a drug reaches the dermal layer, the drugwill perfuse through system circulation.

[0020] An SSP system includes one or more SSP drug perforators,preferably at least 20-200 in an area of about 1 cm², at least one orwhich is formed as a solid matrix of one or more needles or blades, eachpointed or sharpened at a first end for perforation of the skin. Eachperforator is strong and intact enough to pierce the stratum corneum,and is either biodegradable or dissolvable when the perforator (anddrug) has penetrated into the patient's body with body fluid and/orsolvent in the drug reservoir. The biodegradation or dissolution processmay occur over a time interval of between a few tens of seconds and afew hours, with preference being given to shorter time intervals. FIGS.2A-2G are perspective views of individual matrix shapes that aresuitable for use with an SSP system. The matrix in FIG. 2A is a conewith a cusp-like point that may provide extra penetration power. Thematrix in FIG. 2B is a conventional cone shape with a conventionallinear penetration point. The matrices in FIGS. 2C and 2D arecylinder-plus-cone shape for a circular cylinder and for a rectangular(or, more generally, polygonal) cylinder, respectively. The matrix inFIG. 2E is a polygonal cone shape. The matrices in FIGS. 2F and 2Gprovide sequences of one or more sharp or slicing blades (straight orserrated) that contact and penetrate the skin. Other shapes with apointed or blade end can also be used here. The SSP (system) perforatorsillustrated in FIGS. 2A-2G have various shapes and include the solidmatrix material and the selected (first) drug within the matrix material(interstitially distributed or otherwise).

[0021] The SSP perforators can have straight or tapered shafts or can bepyramids or wedges or blades, as illustrated in FIGS. 2A-2G. In apreferred embodiment, the outer diameter of an SSP perforator isgreatest at the base or second end, about 1-1000 μm, and the perforatorouter diameter near the first end is preferably 10-100 μm. The length ofan SSP perforator is typically in a range 1-2000 μm, more preferably ina range 100-1000 μm. The skin is not a smooth and rugged surface and hasdifferent depths microscopically. In addition, the thickness of thestratum corneum and elasticity of the skin varies from person to personand from location to location on any given person's body. A desirablepenetration depth has a range, rather than a single value, for effectivedrug delivery and relatively painless and bloodless penetration.Penetration depth of an SSP perforator can affect pain as well asdelivery efficiency. In transdermal applications, the “penetrated depth”of the SSP perforator is preferably less than 100 mm so that aperforator, inserted into the skin through the stratum corneum, does notpenetrate past the epidermis. This is an optimal approach to avoidcontacting nerves and blood vessels. In such applications, the actuallength of the SSP perforator can be longer because the basal layerassociated with the SSP system may not be fully inserted into the skinbecause of elasticity and rough surface of the skin.

[0022] However, depending upon medical needs, perforator penetration tothe dermis may be required in some applications. In these instances, useof a SSP system can be a practical option in handling instant drugdelivery situations. The penetrating portion of an SSP perforator can beoptimized by adjusting perforator variables (SSP length, dimension,mechanical properties of basal or substrate layer as well as stroke andspeed of insertion of an SSP perforator), as well as accounting fortarget skin elasticity, skin hardness and surface roughness.

[0023] A basal layer (shown in FIGS. 3 and 10) provides protection toisolate a perforated skin region from contamination, and the basal layercan contain anti-bacterial agents and can create occlusion to hydrateperforated skin to enhance flux of fluids. A portal channel likely willcontract or expand depending on the Perforator material properties afterthe SSP perforator dissolves or swells.

[0024] The primary functions of an SSP perforator are to pierce thestratum corneum, to provide prompt initiation and cut-off of drugdelivery, and optionally to help keep the channel open for subsequentdrug delivery or body fluid monitoring. As long as an SSP perforatordissolves reasonably quickly and is strong enough to pierce the stratumcorneum, any biocompatible material can serve as an SSP perforator.

[0025] In preparing an SSP perforator, a mold is prepared usingprecision machining, micro-machining (such as MEMS), or laser-based orelectro-discharge machining. When the mold is prepared, a liquidsolution, including the matrix material and including the selecteddrug(s), is cast in the mold and dried. Depending on the viscosity andother physical and chemical properties of the liquid solution,additional force such as centrifuge force or compression force may beneeded to fill the mold. To form a solid solution, the solvent needs tobe air-dried, vacuum-dried or freeze-dried. Once a solid solution isformed, an SSP perforator is separated from the mold and cut to anappropriate shape and size.

[0026] Where a powder form is used for the SSP material, a mixed powderis spread over the mold. Depending upon the chemical and physicalproperties of the powder, appropriate heating of the powder may beapplied to melt or insert viscous materials into the mold.Alternatively, the powder may be inserted into the mold by pressureand/or application of heating, with or without use of binding agents.When SSP perforators have been formed into an array, the SSP array iscooled, separated from the mold, and incorporated into an SSP system.

[0027] Another suitable approach for SSP fabrication is photo-crosslinking. A polymer solution including a photo-initiator is cast on themold and is solidified by irradiation. Once the solution is solidified,the solid solution can be peeled off and cut and shaped to appropriatesize. Another feasible approach for making perforators is fabrication ofa plurality of micro-fibers that are spooled, arrayed and combined in aplunger.

[0028] Suitable matrix materials for an SSP perforator include polymers,including but not limited to polyvinylpyrolidone (PVP), polyethyleneglycol (PEG), polyvinyl alcohol (PVA), cellulose, hydroxypropylcellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropylmethylcellulose (HPMC), dextrin, mono- and polysaccharide, sodiumcarboxymethyl cellulose, polyalcohol, gelatin, gum arabic, alginate,chitosan cylcodextrin and other biopolymers.

[0029] Carbohydrate derivatives, such as sugar derivatives (trehalose,glucose, maltose, lactose, maltulose, iso-maltulose, lactulose,fluctose, turanose, melitose, melezitose, dextran, maltotol, sorbitol,xylitol, palatinit and mannitol) can be used. Water-soluble ingredients,such as phosphate, nitrate and carboxylate glasses, magnesium chloride,potassium chloride and calcium chloride can be also used for a matrixmaterial, alone or mixed with a matrix polymer.

[0030] Other examples of suitable matrix materials include non-ionichydrophilic or ionic surfactants or lipophilic additives selected fromamong alkylglucosides, alkylmaltosides, alkylthioglucosides, laurylmacrogolglycerides, polyoxyethylene alkyl ethers, polyoxyethylenealkylphenols, polyethylene glycol fatty acids esters, polyethyleneglycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acidesters, polyoxyethylene-polyoxypropylene block copolymers, polyglycerolfatty acid esters, polyoxyethylene glycerides, polyoxyethylene sterols,derivatives, and analogues thereof, polyoxyethylene vegetable oils,polyoxyethylene hydrogenated vegetable oils, reaction mixtures ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols,tocopherol polyethylene glycol succinates, sugar esters, sugar ethers;sucroglycerides, and mixtures thereof.

[0031] An ionic surfactant may be selected from among alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fattyacid derivatives of amino acids, carnitines, oligopeptides, andpolypeptides; glyceride derivatives of amino acids, oligopeptides, andpolypeptides; acyl lactylates; mono-diacetylated tartaric acid esters ofmono-diglycerides; succinylated monoglycerides; citric acid esters ofmono-diglycerides; alginate salts; propylene glycol alginate; lecithinsand hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins;lysophospholipids and derivatives thereof; phospholipids and derivativesthereof; salts of alkylsulfates; salts of fatty acids; sodium docusate;and mixtures thereof.

[0032] A lipophilic additive is selected from among alcohols,polyoxyethylene alkylethers, fatty acids, bile acids, glycerol fattyacid esters, acetylated glycerol fatty acid esters, lower alcohol fattyacids esters, polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters, polypropylene glycol fatty acidesters, polyoxyethylene glycerides, lactic acid derivatives ofmono/diglycerides, propylene glycol diglycerides, sorbitan fatty acidesters, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene-polyoxypropylene block copolymers, transesterifiedvegetable oils, sterols, sterol derivatives, sugar esters, sugar ethers,sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylenehydrogenated vegetable oils, reaction mixtures of polyols and at leastone member of the group consisting of fatty acids, glycerides, vegetableoils, hydrogentated vegetable oils, and sterols, and mixtures thereof.

[0033]FIG. 3 is a plan view of a patch system formed over an array ofSSP perforators 31 that are optionally surrounded by a basal layerincluding an annular region 33 containing adhesive and an anti-bacterialagent (optional), to isolate the perforation region from other regionson the patient's skin. The annular region 33 of adhesive is intended tohold the SSP system to the skin and to prevent, or reduce the likelihoodof, entry of foreign matter and/or external infection. Optionally, adrug reservoir (not shown in FIG. 3) may be located above the SSPperforator array 31 and/or may also be enclosed by the annular region 33of adhesive.

[0034]FIG. 4 is a sectional side view illustrating a perforationactivation mechanism 40 that causes one or more SSP perforators 41 topenetrate, or withdraw from, the patient's skin 42 to initiate and/orcut off delivery of a drug contained in the perforator(s). Initiation orcut off of drug delivery can occur in as little as about 5 minutes, byinsertion or removal of the SSP perforator(s) 41. Depth of perforatorpenetration is adjusted by a perforation adjustment mechanism, 43A and43B (optional), such as a knob or screw. An SSP perforator 41 is driveninto the patient's skin 42 by a spring or similar mechanism 44 that iscontrolled by a perforation mechanism trigger 45.

[0035]FIG. 5 is a sectional side view illustrating a perforationactivation mechanism 50 in which one or more SSP perforators 51 isdriven into, or withdrawn from, the patient's skin 52 by a screw 54 thatis controlled by a screw knob or motor or similar device 55.

[0036]FIG. 6 is a sectional side view illustrating a perforationactivation mechanism 60 in which one or more SSP perforators 61 is urgedinto the patient's skin 62 by a vacuum device 65, then injected by aspring 64 that causes the perforators 62 to be extended from, orwithdrawn into, an activation housing 66. Application of a mild vacuumin the skin perforation region may help to reduce skin variability.

[0037]FIG. 7 is a sectional side view illustrating a perforationactivation mechanism 70 in which one or more SSP perforators 71 isdriven into, or withdrawn from, the patient's skin 72 by a gas expansionmechanism 74 including a gas pressure chamber 75 and a gas reservoir 76.

[0038]FIG. 8 illustrates one means by which the perforator mechanismsshown in FIGS. 4, 5, 6 and/or 7 may be used to control or vary movement,including but not limited to penetration depth, of the corresponding SSPperforators 82 into or out of the patient's skin 81. This design can beused with laparoscopes or endoscopes for internal drug delivery.

[0039]FIG. 9 is a sectional side view illustrating a perforationactivation mechanism 90 in which one or more SSP perforators 91 isdriven into the patient's skin 92 by pressure, manually applied by afinger or other pressure mechanism 93, to one side of the perforator(s).

[0040] Optionally, a drug patch system 100, illustrated in FIG. 10,includes a drug reservoir 101, containing a second drug that may be thesame as or different from the first drug, that is located above andadjacent to the SSP perforator array 102 and that has an independentlycontrolled reservoir drug delivery system 103. The drug patch system 100preferably includes a backing film 104 that surrounds the drug reservoir101 and includes an annular adhesive region 105 (basal layer, bestillustrated in FIG. 3) that surrounds and seals off the SSP skinperforation region 106. A plastic release liner 107 is peeled off beforeskin perforation and protects an SSP system until the liner is peeledoff.

[0041] In a preferred embodiment, the reservoir in a patch systemcontains a drug and optionally contains a chemical enhancer in a liquidreservoir, a skin anti-irritant, an anti-infection chemical and/or otherchemicals in liquid form. The chemical enhancer may be a fatty alcohol,an acid, an ester, a surfactant, a macrocyclis, a terpene, aphospholipid, a pyrrolidone, an amide or an amino acid. Moreparticularly, a chemical enhancer may be drawn from among alkyl alcohol,alpha bisabodol, decyl alcohol, dexpanthenol, dodecanol, etylene glycol,fatty alcohols, glycerol, hexadecanol, isopropanol, octadecanol,tetrahydrofurfuryl alcohol, trichloroethanol, trifluoroethanol, alkylacetamide, crotamiton, lauryl diethanolamide, toluamide, dimethylacetamide, dimethyl formide, formamide, nicotainamide, acyl-amino-acids,alanine, arginine, proline, serine, aspartic acid, cysteine, glutamicacid, glycine, valine, leucine, isoleucine, protein aprotinin, azone,essential oils, such as carvone, cineole, eucalyptol, eugenol, methol,methone, terpene fatty acids, such as carboxyl acid, capric acid,diisopropyladipate, isopropyl myristate (IPM), isostearic acid, glycerylmonolaurate (GML), glycerol monooleate (GMO), lactic acid, linoleicacid, lauric acid, methyl laurate, methyl myristate, oleic acid,polyethylene glycol monolaurate, sorbitan monooleate (SMO), sucrosecocoate, sucrose monoloaurate, sucrose monooleate, triglyceride,macrocyclic enhancers, such as cyclodextrin, cyclopentadecanone andcyclopentadecanolide, phospholipids, phospholipid/phosphate enhancers,such as dialkylphospahte, lecithin, dioxane, dioxolane, alkylsulfones,alkylsulfones, cetyl ether, cyclic dimethylsiloxane,decamethyltetrasiloxane, dialkyl sulfoxides, dimethylsulfoxide,decylmethylsulfoxide, hexamethyldisiloxane, methyl octylsulfoxide, alkylammonium bromide, benzyl nicotinate, butylazocyclopentane, capsaicin,calcium thioglycolate, cyclic amine, diethyl sebacate, dimethylaminoacetate, ethylene glycol monoethyl ether, imidazole, methylorthoformate,oxazoline, proline, urea, urethane, macrocyclis, amines, alkylpyrolidones, N-methyl pyrrolidone, ethyl pyrrolidone, pyrrolidone,hydroxymethyl pyrrolidone, hexyl pyrrolidone, lauryl pyrrolidone,pyrrolidone-carboxylic acid, lauryl pyrrolidone carboxylic acid,pyroglutamic acid, sodium dedecyl sulfate, sodium deoxycholate, sodiumlauryl sulfate, sorbitan monopalmitate, sorbitan trioleate, soybeancasein, terpenes, piperazine derivatives, sodium traurocholate,liposome, bisbolol, dithiothreitol and vitamin E (α-tocopherol).

[0042] FIGS. 11A/11B/11C are sectional side views illustrating apreferred embodiment of an SSP patch insertion process in a transdermalapplication. In FIG. 11A, adhesive in a basal layer 111 of an SSP patch110 is applied to the skin 112 to hold the patch against the skin. Atthis point, the perforators 113 are displaced from the skin 112. In FIG.11B, a plunger or other mechanism 114 is activated to move theperforators 113 into contact with the skin 112, to penetrate the stratumcorneum and to enter the epidermis or dermis. In FIG. 11C, theperforators 113 and a basal layer 115 remain in contact with the skin112. In a preferred embodiment, drug molecules in a reservoir within theupper reservoir of the SSP patch system flow through the channel createdby a fully or partially dissolved SSP perforator and into the epidermis.The drug molecules then diffuse into the dermis for local treatment orfor transport through the body.

[0043] An SSP patch system preferably includes a reservoir containing aliquid or gel form of the second drug and one or more perforatorsextending from at least a part of the reservoir's surface. The SSPperforators associated with the patch system penetrate the stratumcorneum of the skin to enhance percutaneous drug administration and toprovide prompt drug delivery and/or prompt drug cut off. In the patchsystem, the SSP perforators and the reservoir can be constructed as asingle unit or as separate units.

[0044] The patch reservoir is intended to provide sustained,controllable delivery of a liquid or semi-liquid (second) drug into oracross a biological barrier so that diffusion channels are created andremain open after insertion and dissolution of an SSP perforator (matrixplus drug). The size, shape, composition and areal density of SSPperforators affect the drug release rate through the skin channels.Alternatively, other control mechanisms such as iontophoresis,sonophoresis, heating components and mechanical vibration forces canaccelerate, decelerate or otherwise control drug transport through thestratum corneum.

[0045] An SSP patch system is applied to the skin so that one or moreSSP perforators penetrate through the stratum corneum, into theepidermis or into the dermis depending on the application. In apreferred embodiment, drug molecules in a reservoir in an SSP patchsystem flow through the channel created by a fully or partiallydissolved SSP perforator and into the epidermis or dermis. The drugmolecules diffuse into the dermis for local treatment or for transportthrough the body.

[0046] An SSP system can transport therapeutic and/or prophylacticagents, including drugs and vaccine and other bio-active molecules,across skin and other tissues. An SSP device permits drug delivery andaccess to body fluids across skin or other tissue barriers, with minimaldamage, pain and/or irritation at the tissue. In drug deliveryapplications, an SSP perforator optionally is primarily composed of anactive drug and a dissolving or swelling solid matrix depending on adesired drug profile. The SSP system acts as immediate drug source andas a channel creator for subsequent drug delivery through skin. In adiagnostic application, an SSP perforator contains no drug and iscomposed substantially entirely of a fast-dissolving, biologicallyinactive solid or a dissolvable or swellable matrix for creating andmaintaining the channels. Depending on the application, an osmoticallyactive or anti-irritant compound can have a beneficial effect. In somediagnostic applications and SSP perforator can include or consist ofsensor materials that react to presence of specific analytes.

[0047] A primary function of a basal layer in an SSP system withreservoir to separate the drug reservoir and to serve as a transportbridge between the reservoir and the remainder of the system. The basallayer material can be same as the solid matrix material, or may be adifferent material, depending on the application. In an SSP systemwithout reservoir, the basal layer can be laminated with one or moreadditional layers or materials for controlled release. The outermostbasal layer can act as an impermeable backing film to protect againstany virus or bacterium that might otherwise invade the skin perforationregion. In order to avoid back diffusion from other parts of the SSPsystem, this layer should have low drug solubility. Where additional andsustained drug release is required, the basal layer can be constructedto contain more of a drug or to provide a conduit to a secondaryreservoir. It is useful to have anti-virus and/or anti-bacterialprotection in the basal layer to suppress infection. In order to vary orcontrol the drug delivery rate, an external physical enhancement system,using iontophoresis, or sonophoresis, piezoelectric response or asimilar response, can be provided as part of a basal layer and/or anoverlay layer.

[0048]FIG. 12A illustrates a simple design of an SSP patch 120A,including a basal layer 121 including a backing and an array of one ormore perforators 122 located adjacent to the skin 123. Activeingredients (drug or drug solid solution) are contained in theperforator. The basal layer can have different thicknesses but is mostoften an impermeable backing layer. This design is ideal for potent drugdelivery, for administrating small doses or for instant drug delivery.

[0049]FIG. 12B illustrates another design of an SSP patch 120B,including an array of perforators 122 and a basal layer 124 that isporous and optionally serves as a drug reservoir. Active ingredients arecontained in the perforator and in the basal layer. The basal layer 124can have different composition from the SSP perforator(s) outermostlayer but is most often an impermeable backing layer. This design isalso ideal for potent drug delivery, for administrating small dosessystemically, or for topical applications.

[0050]FIG. 12C illustrates a more complex design of an SSP patch 120C.Active ingredients are contained in the perforator and in the reservoir.A top portion of the basal layer 126 contains a drug reservoir patch125. A first set of perforators 122-1 is oriented to penetrate thestratum corneum of the skin 123, and a second set of perforators 122-2is oppositely oriented to penetrate a membrane that surrounds orcontains fluid in the reservoir patch 125. The reservoir patch 125 canbe applied after SSP system application or can be combined with SSPlayers. The reservoir can have a variety of composition or formulationdepending on targeted drug release profile.

[0051]FIGS. 12D and 12E illustrate other designs, 120D and 120E, of SSPpatch systems modified from FIGS. 12B and 12C, respectively. Theperforator does not contain any drug but does include a dissolvingmatrix; active ingredients are contained in the basal layer and/orreservoir only. Depending on the drug solubility and concentration, drugrelease from the basal layer can be controlled. The systems shown inFIGS. 12D and 12E are used primarily for diagnostic purposes and forsustained drug release applications, respectively.

[0052]FIG. 12F illustrates use of swellable materials as part of an SSPpatch system 120F, optionally with no drug(s) included in the perforatorsolid matrix. This design extends skin channel openings for a longer (orshorter) time interval and extends the duration of drug delivery or isused for diagnostic applications.

[0053] Any drug or other bioactive agent can be delivered using the SSPsystem. Delivered drugs can be can be proteins, peptides, DNA, genes,polysaccharides, and synthetic organic and inorganic compounds.Representative agents include, but are not limited to, anti-infectives,hormones, growth regulators, drugs regulating cardiac action or bloodflow, and drugs for pain control. The drug can be for local treatment orfor regional or systemic therapy. The following are representativeprotein drug examples dose peŕ injection they are used to treat:α-interferon 11-100 μgm β-interferon for multiple sclerosis 22-44 μgmErythropoetin for anemia 10-30 μgm Follicle stimulating hormone (FSH)5-30 μgm Granulocyte Colony Stimulating Factor 9-15 μgm (G-CSF)Granulocyte Macrophage Colony Stimulating 250 μgm Factor Human chorionicgonadotropin 30-300 μgm Leutinizing hormone 2-30 μgm Salmon Calcitonin25-50 μgm Glucagon 1 mgm GNRH antagonist 2 mgm Insulin 0.75-1.5 mgmHuman Growth Hormone (GHD) 0.25-1.5 mgm Human Growth Hormone (AIDS) 6mgm Testerone 5-10 mgm Lidocaine 2-5 percent Diclofenac Sodium 100 200mgm Oxybutynin 5-15 mgm Ketoprofen 75-200 mgm Alemdronate 10 mgmEnalpril Maleate 10-40 mgm Phenylpropanolamine HCl 75 mgm Cromolynsodium 3.2-10 mgm Isotretinoin 0.5-2 mgm/Kgm Oxytocin 1-2 unit/min/ivParoxetine HCl 20 mgm Flurbiprofen 100 mgm Sertaline 50 mgm Venlafaxine75 mgm Leuprolide 0.125-0.25 mgm Risperidone 4-6 mgm Galanthaminehydrobromide 16-24 mgm Enoxaprin, anticoagulant Etanercept, rheumatoidarthritis Fentanyl, postoperative and chronic pain Filgrastin, low whiteblood cells from chemotherapy Heparin, anticoagulant Parathyroid hormone(PTH) Somatropin, growth hormone Sumatriptan, migraine headachesMorphine Opiate anti-arthritis.

[0054] Many drugs can be delivered at a variety of therapeutic rates,controlled by varying a number of design factors including: dimensionsof the SSP, dissolving rate of the matrix, number of SSP perforators,size of the SSP patch, size and composition of the reservoir, andfrequency of using the device. For example, devices designed to deliverdrug at high rates might have a more active drug loaded SSP and/or afaster dissolving matrix. For sustained drug release, fewer SSPperforators and/or use of a slow(er) dissolving solid matrix are useful.The SSP patch can be applied to the skin or other tissue to deliverdrugs continuously or intermittently or at a varying rate, for timeintervals ranging from a few seconds to several hours or days. Mostapplications of SSP drug transdermal delivery would target theepidermis, although delivery into blood stream directly is available byextending the penetration length of an SSP patch.

[0055] The SSP patch systems disclosed herein are also useful forcontrolling transport across tissues other than skin. For example, anSSP patch can be inserted into a patient's eye to control or correctconjunctiva, sclera, and/or cornea problems, to facilitate delivery ofdrugs into the eye with a slow moving actuator. Similarly, an SSPsystem, inserted into the eye, could facilitate transport of fluid outof the eye, which may be of benefit for treatment of glaucoma. An SSPpatch can also be inserted into the buccal (oral), nasal or vaginalregions or inside a tissue with the aid of a laparoscope or into otheraccessible mucosal layers to facilitate transport into or across thosetissues. For example, a drug may be delivered across the buccal mucosalfor local treatment in the mouth. As another example, SSP systems may beused internally within the body on, for example, the lining of thegastrointestinal tract to facilitate uptake of orally-ingested drugs orat the lining of blood vessels to facilitate penetration of drugs intothe vessel wall. In this case of internal tissue application, use ofbio-adhesive SSP material can be an additional benefit.

[0056] Another important application is vaccination. The skin is anideal site for effective vaccine delivery because it contains a networkof immune cells, such as Langerhans cells. There are several advantagesof SSP technology in delivering antigenic compounds to the epidermis,which has a high density ofimmune cells and consequently triggers theimmune system more effectively. An SSP system is a practical design fordeveloping multivalent vaccines easily and is expected to provide morestability than use of a liquid for transport and storage of drugs. Thefollowing vaccines can be delivered, among others.

[0057] Hepatitis B

[0058] HIV vaccine

[0059] Influenza

[0060] Diphtheria

[0061] Tetanus

[0062] Pertussis

[0063] Lyme disease

[0064] Rabies

[0065] Pneumococcus

[0066] Yellow fever

[0067] Cholera

[0068] Vaccinia

[0069] Tuberculosis

[0070] Rubella

[0071] Measles

[0072] Mumps

[0073] Rotavirus

[0074] Botulinum

[0075] Herpes virus

[0076] Other DNA vaccines

[0077] Another area of applications is cosmeceutical. An SSP systemincluding a patch can deliver botox toxin or a hydroxyacid moreefficiently and safely to remove or reduce wrinkle formation and skinaging. The system is also useful for treating lesions or abnormal skinfeatures, such as pimples, corns, warts, calluses, bunions, actinickeratoses and hard hyperkeratotic skin, which is often found on theface, arms, legs or feet. An SSP system is also useful as a food patchto deliver essential amino acids, fats and vitamins. A food patch isoften used in emergencies.

What is claimed is:
 1. A system for controlled delivery of one or moredrugs to a patient's body, the system comprising: an array of one ormore substantially solid drug solution delivery perforators, with eachperforator having a first end with at least one point or blade adaptedfor penetrating skin and for providing a skin aperture on a patient'sbody, with at least one of the perforators including a matrix materialthat is dissolvable, swellable or biodegradable within a selected timeinterval when the perforator is positioned within the patient's body,and including a first selected drug distributed within the matrix, wherethe perforator array can be positioned adjacent to a selected region ofthe patient's skin; and an activatable pressure mechanism, associatedwith the at least one perforator, for causing the at least oneperforator to penetrate the patient's skin at the selected region, inresponse to activation of the pressure mechanism.
 2. The system of claim1, wherein said at least one perforator comprises a matrix material thatis at least one of a polymer, a carbohydrate derivative, a water-solubleglass, a water-soluble halide, a non-ionic hydrophilic surfactant, anionic surfactant and a lipophilic additive.
 3. The system of claim 1,wherein said at least one perforator comprises a matrix material that is100 percent drug.
 4. The system of claim 1, wherein said at least oneperforator comprises a solid matrix material having at least oneselected drug distributed within the matrix, where the drug is at leastone of a protein, a peptide, a DNA component, a gene, a polysaccharide,a vaccine, a synthetic organic compound and a synthetic non-organiccompound.
 5. The system of claim 1, wherein said at least one perforatoris positioned to penetrate said skin to an epidermal layer of said skin.6. The system of claim 1, wherein said at least one perforator ispositioned to penetrate said skin to a dermal layer of said skin.
 7. Thesystem of claim 1, wherein said pressure mechanism provides adjustmentof skin penetration depth of said at least one perforator.
 8. The systemof claim 1, wherein said pressure mechanism is adapted to withdraw saidat least one perforator from said patient's skin, after said at leastone perforator has penetrated said patient's skin.
 9. The system ofclaim 1, wherein said pressure mechanism is drawn from a group of skinpenetration mechanisms consisting of an activatable spring, a screwdriven by an activatable screw motor, a gas pressure-driven device and amanually operated perforator.
 10. The system of claim 1, wherein saidpressure mechanism, when activated, drives said at least one perforatorinto said patient's skin a selected distance in a range of 10-1000 μm.11. The system of claim 1, wherein said first end of said at least oneperforator is a needle having a cross-sectional shape that is polygonal.12. The system of claim 1, wherein said first end of said at least oneperforator is a needle having a cross-sectional shape that is cusp-like.13. The system of claim 1, wherein said first end of said at least oneperforator is a blade.
 14. The system of claim 1, wherein said at leastone perforator has an outer diameter near said first end in a range of10-100 μm.
 15. The system of claim 1, further comprising a fluidreservoir, in fluid communication with said skin aperture and having afluid container adapted for receiving and holding a selected amount of asecond selected drug.
 16. The system of claim 15, wherein said reservoircomprises a patch reservoir that receives and holds said second drug,and said first and second drugs are substantially the same.
 17. Thesystem of claim 15, wherein said reservoir comprises a patch reservoirthat receives and holds said second drug, and said first and seconddrugs are different from each other.
 18. The system of claim 15, whereinsaid reservoir comprises a patch reservoir having an annular region ofadhesive that surrounds and contacts said selected region on saidpatient's skin.
 19. The system of claim 18, wherein said adhesivecomprises a substance that is anti-bacterial.
 20. The system of claim16, further comprising a second array of perforators, located adjacentto said first array of perforators, with at least one perforator in thesecond array having a first end with at least one point or blade andbeing oriented so that the at least one perforator in the second arrayand said fluid container can be moved relative to each other to provideat least one aperture in said fluid container.
 21. The system of claim15, wherein said reservoir contains a fluid comprising a chemicalenhancer drawn from a group consisting of a fatty alcohol, an acid, anester, a surfactant, a macrocyclis, a terpene, a phospholipid, apyrrolidone, an amide and an amino acid.
 22. The system of claim 15,further comprising a drug introduction mechanism that permits flow ofsaid second drug from said reservoir to said at least one perforatoraperture in said patient's skin when said pressure mechanism has beenactivated.
 23. The system of claim 1, wherein said array of perforatorsincludes at least 20 of said perforators in a region having an area nomore than 1 cm².
 24. The system of claim 1, further comprising at leasta second of said perforators that includes a second matrix material thatis dissolvable, swellable or biodegradable within a selected second timeinterval, when positioned within said patient's body, and substantiallyno drug is distributed within the second matrix material.
 25. A systemfor diagnosis of a selected body fluid in a patient's body, the systemcomprising: an array of one or more solid perforators, with eachperforator having a first end with at least one point or blade adaptedfor penetrating skin and for providing a skin aperture on a patient'sbody, with at least one of the perforators including a matrix materialthat is dissolvable, swellable or biodegradable within a selected timeinterval when the perforator is positioned within the patient's body,where no drug is distributed within the matrix and where the perforatorarray can be positioned adjacent to a selected region of the patient'sskin; and an activatable pressure mechanism, associated with the atleast one perforator, for causing the at least one perforator topenetrate the patient's skin at the selected region, in response toactivation of the pressure mechanism.